Increased expression of inhibitor of apoptosis proteins, survivin and XIAP, in non-small cell lung carcinoma

Abstract

Abstract.Members of the inhibitor of apoptosis protein (IAP) family, survivin and X-chromosome-linked IAP (XIAP), contribute to apoptosis resistance of cancer cells, and an increase in their expression may elevate the apoptotic threshold of malignant tumours during their growth and progression. In the present study, we investigated the expression status of survivin and its interactants hepatitis B X-interacting protein (HBXIP) and XIAP in non-small cell lung carcinoma (NSCLC) cell lines and NSCLC tumours and matched lungs from surgically treated patients in relation to their clinicopathological data. The expression of survivin, HBXIP and XIAP mRNAs was quantitated by real-time RT-PCR. The expression of survivin and XIAP proteins was analysed by Western blotting and ELISA. Survivin mRNA and protein levels were highly upregulated in NSCLC cells and tissues as compared to the lungs. In fact, the levels of survivin mRNA and protein in the tumours were more than 10-fold higher in 96 (64%) and 72 (82%) of the 150 and 88 examined NSCLC patients, respectively. The expression of survivin mRNA was higher in squamous cell lung carcinomas than in lung adenocarcinomas (LACs; P=0.003) and in less-differentiated tumours than in well-differentiated ones (P=0.007). The level of survivin protein was higher in stage IB and stage II+III tumours (P=0.049 and P=0.044), than in stage IA tumours. The BIRC5 promoter polymorphism at nucleotide -31 did not influence the expression of survivin mRNA and protein in NSCLC cells and tumours. HBXIP mRNA was abundantly expressed in NSCLC cell lines and NSCLC tumours and lungs, while its level was comparable in the tumours and lungs. The expression of XIAP mRNA in NSCLC cell lines and NSCLC tumours and lungs was not significantly different. However, the expression of XIAP protein was higher in NSCLC tumours, particularly in LACs, as compared to the lungs (P=0.017 and P=0.004). In conclusion, the overexpression of survivin in the majority of NSCLCs together with the abundant or upregulated expression of HBXIP and XIAP suggest that tumours are endowed with resistance against a variety of apoptosis-inducing conditions.

The Chinese Herb Isolate Isorhapontigenin Induces Apoptosis in Human Cancer Cells by Down-regulating Overexpression of Antiapoptotic Protein XIAP

“…There is growing evidence showing the correlation between XIAP overexpression and malignant cancer aggression (4), drug resistance (26), and poor clinical prognosis in many malignancies (27). Poorly differentiated carcinomas also display significantly higher levels of XIAP expression than well differentiated carcinomas (28). Thus, down-regulation of XIAP expression and inhibition of XIAP function attract a great deal of attention in the field of cancer therapy.…”

The Soy Isoflavone Equol May Increase Cancer Malignancy via Up-regulation of Eukaryotic Protein Synthesis Initiation Factor eIF4G

“…Of the proteins that were elevated in response to equol, IRES-containing cyclin D1 and c-Myc up-regulation are hallmarks of cancer that have been directly associated with eIF4G up-regulation (32, 33, 42, 68 -70). The cell survival genes survivin, Bcl-2, and Bcl-XL and the angiogenesis promoter VEGF are also sensitive to eIF4G levels, have IRES sites, and are elevated in aggressive cancers (71)(72)(73)(74).…”

KLF5 promotes hypoxia-induced survival and inhibits apoptosis in non-small cell lung cancer cells via HIF-1α

“…Apoptosis is controlled by caspase family (29) and caspase-3 plays a key role in both the extrinsic and the intrinsic apoptosis pathways (30). Survivin, as a direct inhibitor of caspase-3, is implicated in promoting tumorigenesis and resisting chemotherapy and radiationinduced apoptosis in non-small cell lung cancer (31). Recent studies show that KLF5 is involved in the upregulation of survivin via direct interaction with p53 (32), and knockout of KLF5 induces caspase-3 cleavage through pERK/MKP-1 signaling.…”